3-alkylthio-17alpha-carboxyethylandrosta-3,5-dien-17beta-ol lactones and process



United States Paten Q 3,004,023 3-ALKYLTHIO-17u-CARBOXYETHYLANDROSTA- 3,5-DIEN-17fl-0L LACTONES AND PRQCESS Robert C. Tweit, Wilmette, 111., assignor to G. D. Searle & Co., Chicago, 11]., a corporation of Delaware N Drawing. Filed Mar. 23, 1960, Ser. No. 16,919 4 Claims. (Cl. 260-43957) This invention relates to 3-alkylthio-17a-carboxyethylandrosta-3,5-dien-l7 3-ol lactones and a process for the manufacture thereof. More particularly, this invention relates to chemical compounds of the formula I O I, Had

CHzCHzCOOZ wherein X and R have the meansings assigned above, and Z represents hydogen, an alkali metal, or the arm monium radical. Those skilled in the art will appreciate that the described salts readily derive from the corresponding lactones on contact with aqueous alkali. The free acids, in turn, are obtained from the salts by a critically brief exposure to a proton source; prolongation of the exposure time induces lactonization.

The compounds to which this invention relates are useful because of their valuable pharmacological properties. For example, they are potent diuretics, being adapted to block the effect of desoxycorticosterone acetate on urinary sodium and potassium.

Manufacture of the subject compounds proceeds by contacting a 3-oxo steroid of the formula '2 with a lower alkyl mercaptan in an alcoholic medium such as methanol, ethanol, 2-propanol, etc., there being a trace of mineral acid present. The definition of R remains as before.

The following examples describe in detail compounds illustrative of the present inventon and methods which have been devised for their manufacture. However, the invention is not to be construed as limited thereby, either in spirit or in scope, since it will be apparent to those skilled in the art of organic synthesis that many modifications, both of materials and of methods, may be practiced Without departing from the purpose and intent of this disclosure. Throughout the examples hereinafter set forth, temperatures are given in degrees centigrade and relative amounts of materials in parts by weight, except as otherwise noted.

EXAMPLE 1 1 7a-carboxyethyl-3-methylthi0andr0sta-3,5 -dien-1 713-0! lactone To a solution of 34 parts of l7u-carboxyethyl-17/3-hydroxyandrost-4-en-3-one lactone, preparable by the procedure described in US. 2,705,712, in 1000 parts of methanol is added 10 parts of liquid methyl mercaptan and 1 part of concentrated sulfuric acid. The precipitate which forms is filtered oif and Washed on the filter with ether. The product thus obtained is l7m-carboxyethyl-3-methylthioandrosta-3,5-dien-17/3-01 lactone, M.P. 237-241", the formula of which is HsCS- EXAMPLE 2 1 7 u-carboxyethyl-3-methy lthzo-J 9-norandrosla-3,5 -dien 1 7fl-ol lactone To a solution of 117 parts of l7oc-carboxyethyl l7 3- hydroxy-l9-norandrost-4-en-3-one lactone, preparable by the procedure described in US. 2,918,463, in 3500 parts of methanol is added 50 parts of liquid methyl mercaptan and 8 parts of concentrated sulfuric acid. The resultant mixture is cooled to insure complete precipitation of the solid product thrown down. The precipitated material, filtered off and Washed on the filter, melts at 166-168. This material is 17n-carboxyethyl-Z-methylthio-l9-norandrosta-3,5-dien-l7;3-ol lactone, of the formula Substitution of 12 parts of ethyl mercaptan for the methyl mercaptan called for in Example 1 aflords, by the a procedure there detailed, l7a-carboxyethyl-3-ethylthio- 4. In a process for the manufacture of compounds of androsta-3,5-dien-l7B-o1 lactone, of the formula the formula 1; 5 Hs H3O HzC I R H5025. lower alkyl-S I What is claimed is: wherein R represents a member of the group consisting of 1. A compound of the formula 15 hydrogen and a methyl radical, the step which comprises contacting a 3-oxo steroid of the formula lower alkyl-S- 0- wherein R represents a member of the group consisting of hydrogen and a methyl radical. with a lower alkyl mercaptan in a liquid alcohol solution 17"carboxyethyl3'methylthioandmsta'35'd1en'1713' 30 containing sulfuric acid, R in the formula of the 3-oxo o1 lactone. t db dfi d bio 3. 17-carboxyethyl-3-methylthio-19-norandrosta-3,5- S erol emg e 116 as e re dien-17,B-ol lactone. No references cited. I

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,004 O23 October 10 1961 Robert Co Tweit It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, lines 61 to 71 and column 4 lines 17 to 28 I the formula, in each occurrence should appear as shown below instead of as in the patent:

Signed and sealed this 8th day of May 1962.-

(SEAL) Attest:

ERNEST W. SWIDER Attesting Officer DAVID L. LADD Commissioner of Patents 

1. A COMPOUND OF THE FORMULA
 4. IN A PROCESS FOR THE MANUFACTURE OF COMPOUNDS OF THE FORMULA 